Amino Acid Residues 253 and 591 of the PB2 Protein of Avian Influenza Virus A H9N2 Contribute to Mammalian Pathogenesis

Mok, Chris Ka Pun; Yen, Hui-Ling; Yu, May; Yuen, Kit M.; Sia, Sin Fun; Chan, Michael Chi Wai; Qin, Gang; Tu, W; Peiris, Malik

doi:10.1128/jvi.00702-11

Cited by 69 publications

(65 citation statements)

References 25 publications

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“…To determine why these 37 H9N2 isolates showed different replication capability in mice, we focused on analyzing the differences in PB2 and HA of theses isolates because these two proteins of AIVs have been demonstrated to play crucial roles in cross-species infection of mammals (23,27,29,30,42). For the PB2 protein, all these isolates had avian type residues 627E and 701D, which are critical for mammalian adaptation (Table 2).…”

Section: Ha-190v Is Responsible For Enhanced Replication Of H9n2 Aivsmentioning

confidence: 99%

“…Two other substitutions (N313D and N496S) in the HA of an H9N2 AIV have been shown to enhance binding to both ␣2,3-linked sialic acid (SA␣2,3) and SA␣2,6 receptors (27). Some amino acid mutations such as A316S in HA and M147L, D253N, A588V, Q591K, E627K, and D701N in PB2 have been identified to play a critical role in enhancing replication of AIVs in mammals (23,(28)(29)(30)(31).…”

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confidence: 99%

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A Single Mutation at Position 190 in Hemagglutinin Enhances Binding Affinity for Human Type Sialic Acid Receptor and Replication of H9N2 Avian Influenza Virus in Mice

Teng

Shen

et al. 2016

J Virol

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H9N2 avian influenza virus (AIV) has an extended host range, but the molecular basis underlying H9N2 AIV transmission to mammals remains unclear. We isolated more than 900 H9N2 AIVs in our 3-year surveillance in live bird markets in China from 2009 to 2012. Thirty-seven representative isolates were selected for further detailed characterization. These isolates were categorized into 8 genotypes (B64 to B71) and formed a distinct antigenic subgroup. Three isolates belonging to genotype B69, which is a predominant genotype circulating in China, replicated efficiently in mice, while the viruses tested in parallel in other genotypes replicated poorly, although they, like the three B69 isolates, have a leucine at position 226 in the hemagglutinin (HA) receptor binding site, which is critical for binding human type sialic acid receptors. Further molecular and single mutation analysis revealed that a valine (V) residue at position 190 in HA is responsible for efficient replication of these H9N2 viruses in mice. The 190V in HA does not affect virus receptor binding specificity but enhances binding affinity to human cells and lung tissues from mouse and humans. All these data indicate that the 190V in HA is one of the important determinants for H9N2 AIVs to cross the species barrier to infect mammals despite multiple genes conferring adaptation and replication of H9N2 viruses in mammals. Our findings provide novel insights on understanding host range expansion of H9N2 AIVs. IMPORTANCE Influenza virus hemagglutinin (HA) is responsible for binding to host cell receptors and therefore influences the viral host rangeand pathogenicity in different species. We showed that the H9N2 avian influenza viruses harboring 190V in the HA exhibit enhanced virus replication in mice. Further studies demonstrate that 190V in the HA does not change virus receptor binding specificity but enhances virus binding affinity of the H9N2 virus to human cells and attachment to lung tissues from humans and mouse. Our findings suggest that more attention should be given to the H9N2 AIVs with HA-190V during surveillance due to their potential threat to mammals, including humans. Since the first isolate of an avian influenza virus (AIV) H9N2 subtype was reported in the United States in 1966, three distinct lineages of H9N2 viruses that caused outbreaks in domestic poultry in Asia have been identified (1, 2). H9N2 is a predominant subtype of AIVs circulating in poultry farms in Asia and the Middle East and has caused substantial economic losses over the past decade (3-9). Although a large amount of H9N2 vaccines, including inactivated and vectored vaccines, have been used in areas of endemicity, outbreaks caused by H9N2 AIVs are still not efficiently controlled. Importantly, H9N2 AIV has been reported to infect mammals, including humans, pigs, and dogs (10-13), indicating that it has an extended host range. It should be noted that several human infections with an H9N2 AIV have been recorded (14,15). Numerous human infections have also been confirm...

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Section: Ha-190v Is Responsible For Enhanced Replication Of H9n2 Aivsmentioning

confidence: 99%

mentioning

confidence: 99%

A Single Mutation at Position 190 in Hemagglutinin Enhances Binding Affinity for Human Type Sialic Acid Receptor and Replication of H9N2 Avian Influenza Virus in Mice

Teng

Shen

et al. 2016

J Virol

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“…The PB2 D253N substitution is in the NP binding and cap binding domain (27). This mutation has been described in an H9N2 backbone to increase replication and pathogenicity in mice (28). The PB2 D253N substitution was not identified in the P1 sample but was seen in 100% of reads in the RCP5 sample.…”

Section: Resultsmentioning

confidence: 95%

“…1 and 2). Mutational analysis revealed two mutations in lineage A (PB2 D253N and NS1/NEP D2N) that are known to increase infectivity and pathogenicity in other viral backgrounds (28,29). While these changes could affect the phenotype, there is evidence that the differing M segments have a large effect, as well.…”

Section: Resultsmentioning

confidence: 99%

Alternative Reassortment Events Leading to Transmissible H9N1 Influenza Viruses in the Ferret Model

Kimble

Angel

Wan

et al. 2014

J Virol

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Influenza A H9N2 viruses are common poultry pathogens that occasionally infect swine and humans. It has been shown previously with H9N2 viruses that reassortment can generate novel viruses with increased transmissibility. Here, we demonstrate the modeling power of a novel transfection-based inoculation system to select reassortant viruses under in vivo selective pressure. Plasmids containing the genes from an H9N2 virus and a pandemic H1N1 (pH1N1) virus were transfected into HEK 293T cells to potentially generate the full panel of possible H9 reassortants. These cells were then used to inoculate ferrets, and the population dynamics were studied. Two respiratory-droplet-transmissible H9N1 viruses were selected by this method, indicating a selective pressure in ferrets for the novel combination of surface genes. These results show that a transfection-based inoculation system is a fast and efficient method to model reassortment and highlight the risk of reassortment between H9N2 and pH1N1 viruses.

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“…Therefore, the Clade 2.3.2.1c H5N1 viruses may have already adapted to poultry before their introduction into migratory birds. Amino acids Q591 (Mok et al, 2011), E627 (Subbarao et al, 1993;Hatta et al, 2001) and D701 (Zhou et al, 2013) in the PB2 protein of the H5N1 viruses suggest that they have not yet adapted to mammalian hosts. No drug-resistance-associated mutations (H274Y in NA; S31N in M2 (Hay et al, 1985;Pinto et al, 1992)) were observed among migratory H5N1 viruses, suggesting that these H5N1 isolates are still sensitive to NA and M2 inhibitors.…”

Section: Molecular Characteristicsmentioning

confidence: 99%

Highly pathogenic avian influenza H5N1 Clade 2.3.2.1c virus in migratory birds, 2014–2015

Chen

Zhang

et al. 2016

Virol. Sin.

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Amino Acid Residues 253 and 591 of the PB2 Protein of Avian Influenza Virus A H9N2 Contribute to Mammalian Pathogenesis

Cited by 69 publications

References 25 publications

A Single Mutation at Position 190 in Hemagglutinin Enhances Binding Affinity for Human Type Sialic Acid Receptor and Replication of H9N2 Avian Influenza Virus in Mice

A Single Mutation at Position 190 in Hemagglutinin Enhances Binding Affinity for Human Type Sialic Acid Receptor and Replication of H9N2 Avian Influenza Virus in Mice

Alternative Reassortment Events Leading to Transmissible H9N1 Influenza Viruses in the Ferret Model

Highly pathogenic avian influenza H5N1 Clade 2.3.2.1c virus in migratory birds, 2014–2015

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